Derivatives of alpha-halo-alpha-benzyl propionic acid

ABSTRACT

A NEW METHOD OF PREPARING L-A-HYDRAZINO-B-PHENYLALKANOIC ACID AND THEIR DERIVATIVES BY DIRECT HYDRAZINO DISPLACEMENT OF A CORRESPONDING A-SUBSTITUTED-B-PHENYLALKANOIC ACID OR DERIVATIVE IS DISCLOSED. THE PREPARATION OF THE NOVEL INTERMEDIATE COMPOUNDS IS ALSO DESCRIBED.

United States Patent 3,734,937 DERIVATIVES 0F oc-HALO-oz-BENZYLPROPIONIC ACID Sandor Karady, Elizabeth, Seemon H. Pines, Murray Hill,Manuel G. Ly, Edison, and Meyer Sletzinger, North Plainfield, N.J.,assignors to Merck & (30., Inc., Rahway, NJ. No Drawing. Filed June 24,1970, Ser. No. 49,540 Claims priority, application Canada, Mar. 25,1970,

Int. Cl. 60% 11/04 US. Cl. 260-395 1 Claim ABSTRACT OF THE DISCLOSURE Anew method of preparing L-u-hydrazino-B-phenylalkanoic acids and theirderivatives by direct hydrazine displacement of a correspondingu-substituted-fi-phenylalkanoic acid or derivative is disclosed. Thepreparation of the novel intermediate compounds is also described.

This invention describes a new method of preparing certain oz hydrazinoB phenylalkanoic acids and their derivatives. More particularly, itdescribes a method of preparing L-u-hydrazino-fl-hydroxyphenyl alkanoicacid and their derivatives. It further describes a method of preparingcertain chemical compounds which are new and useful intermediates in thesynthesis of the above compounds.

It is known in the art that various u-hydrazino-B-phenylalkanoic acidsare useful as decarboxylase inhibitors. It is further known that theD-isomer of these acids is generally inactive and may even beantagonistic to the action of the L-form, thereby reducing its potency.

This invention describes novel and useful chemical compounds and to theprocess for their preparation. More particularly, this inventiondescribes novel compounds which are intermediates in the preparation ofL-whydrazinos-phenylalkanoic acids and their derivatives.

The present invention provides a new method of preparing theL-stereoisomeric compounds of Formula I where R is hydrogen or hydroxy;

R is hydrogen or lower alkyl;

R is hydrogen or lower alkyl;

R is carboxy, loweralkoxycarbonyl, metaloxycarbonyl,

organocatoxycarbonyl, amido or cyano; and

R, is hydrogen or acyl.

It is to be understood that the L-configuration is in reference to theabsolute configuration on the a-carbon in relation to the hydrazine.

This invention further provides new methods of preparing valuableintermediate compounds which are useful in the preparation of thecompounds of Formula I. These intermediate compounds are described byFormula II.

3,734,937 Patented May 22, 1973 where X is chloro, bromo, iodo,arylsulfonyl (such as phenylsulfonyl, 0-, mand p-tolylsulfonyl,acenaphthene-S- sulfonyl, 5 -indanesulfonyl, etc.) loweralkylsulfonyl(such as methylsulfonyl, etc.);

R is hydrogen, hydroxy, lower alkoxy, aralkoxy; and

R R and R are as previously described.

where R and R are as described above.

A most preferred embodiment of this invention describes the preparationof L-u-(3,4-dihydroxybenzyl)-uhydrazinopropionic acid andL-B-(3,4-dihydroxypheny1)- a-hydrazinopropionic acid.

In the above descriptive portions of Formulae IIII, the followingdefinitions apply:

The lower alkyl radical signifies an alkyl group containing from 1 toabout -6 carbon atoms which can be straight chained or branched.

The term metal refers to an alkali or alkaline earth metal.

The term organocatoxy refers to any organic cation formed from apositively charged atom or radical such as cyclohexylamine,triethylamine, phenethylamine and the like. It is formed when thesebases react with the carboxy group to form salts of the structure givenin the formula.

The lower alkoxy radical signifies an alkoxy group containing from 1 toabout 6 carbon atoms which can be straight chained or branched.

Aralkoxy refers to an arylalkoxy group, the aryl portion of which may beone or more phenyl or naphthyl radicals attached to an u-alkoxy radicalwhich contains from 1 to about 4 carbon atoms. The preferable aralkoxygroups are benzyl, diphenylmethyl, trityl, naphthylmethyl andsubstituted benzyl and the like groups. Such substituents may includelower alkyl such as o-methylbenzyl, lower alkoxy such as 3,4-veratryland 4,4,4-trimethoxytrityl and the like.

The acyl radical may be any organic radical derived from an organic acidby the removal of the hydroxyl group. It includes such radicals derivedfrom carboxylic acids, sulfonic acids and the like.

Aryl refers to phenyl, naphthyl and substituted phenyl which may belower alkyl or lower alkoxy substituents.

The present invention may be practiced by condensing a hydrazine, anacyl hydrazine or an alkali-metal salt of a hydrazine with an usubstituted-alkanoic acid or derivative of Formula II. The startingmaterial should be one in which the a-position contains a bromo, iodo,chloro or other good leaving group such as any acylsulfonyl oralkylsulfonyl group. Such leaving groups may be phenylsulfonyl, o-, mandp-tolylsnlfonyl, acenaphthene-S-sulfonyl, S-indanesulfonyl,methylsulfonyl, etc.

When the protected D-amino compound is diazotized it may be converted tothe D-bromo compound of Formula II. This may then be hydrolyzed orreduced to remove any protecting groups on the 3,4-hydroxy positions.Displacement with hydrazine, an acylhydrazine or an alkalimetal salt ofhydrazine may then proceed with inversion to yield L-hydrazino product.

The protected L-amino compound may be used also by carrying out thedisplacement with retention or with two inversions. The protectedL-bromo compound is treated with potassium iodide in alcohol to yieldprotected D-iodo compound which reacts with hydrazine or alkali-metalsalt.

The above displacement reaction may be carried out on the acid, acidsalt, nitrile, amide or ester starting material and result in thehydrazino-acid, hydrazino-nitrile, hydrazino-amide or hydrazino-esterproduct. If desired, after the intermediate is prepared which has theproper a.-leaving group, the acid salt, nitrile, amide or ester may thenbe hydrolyzed to the acid in the conventional manner before the leavinggroup is acted upon by hydrazine. The ester group present may be anyester which will hydrolyze in the conventional manner but preferably isthe lower alkyl ester.

The following reaction sequence describes the method of this invention:

1 CH-C-Ra HNNH:

EXAMPLE 1 To a mixture of 23.9 g. (0.1 mole) of L-oc-aminO-zx-(3,4-dimethoxybenzyl)propionic acid [J. Org. Chem. 29, 1424 (1964)] in200 ml. of acetic acid containing 10% by weight of hydrogen bromide isadded 10.35 g. (0.15 mole) of sodium nitrite in 20 ml. of water 5-10" C.The mixture is stirred for two hours at 5l5 C. then cautiously withstirring warmed to 50 C. The mixture is filtered through sintered glass,the filtrate concentrated in vacuo. The residue is taken up inchlorofrom, Washed with water, dried over magnesium sulfate andconcentrated. The residue is crystallized from methanol-water to obtainL-oL-br0mO-a-(3,4 dimethoxybenzyl)propionic acid.

A mixture of L-a-bromo-u-(3,4-dimethoxybenzyl)propionic acid (38.8 g.,0.13 mole) and 600 ml. of concentrated hydrochloric acid are heated in asealed tube at C. for 2 hours. The resulting mixture is evaporated todryness in vacuo and the product extracted out with ethanol andevaporated to dryness to obtain L-u-bromooc- 3,4-dihydroxybenzylpropionic acid.

To a solution of 27.5 g. (0.1 mole) of L-u-bromo-a(3,4-dihydroxybenzyl)propionic acid in 200 ml. of methanol is added 20g. of potassium iodide and the mixture is refluxed for 2 hours. Themixture is cooled, 5.0 g. of 96% hydrazine added and the mixture againrefluxed for 2 hours. On cooling, the mixture is concentrated to drynessin vacuo, the residue taken up in chloroform-water, the chloroformsolution Washed with water and saturated salt solution and thechloroform extract dried over magnesium sulfate. The mixture isconcentrated to dryness and the residue crystallized from methanol-waterto obtain L u (3,4-dihydroxybenzyl)-a-hydrazinopropionic acid (M.P. 208dec.).

When L a amino 0c (3,4-dimethoxybenzyl)propionic acid is replaced in theabove procedure by L-ocamino a (3 methoxybenzyl)propionic acid,L-fi-(3,4- dimethoxyphenyl)-a-aminobutanoic acid orL-a-aminofl-(3,4-dimethoxyphenyl)propionic acid, the product obtained isL a (3-hydroxybenzyl)-u-hydrazinopropionic acid, L ,3 (3,4dihydroxyphenyl) 0c hydrazinobutanoic acid or L f3 (3,4dihydroxyphenyl)-u-hydrazinopropionic acid.

When L a amino a (3,4-dimethoxybenzyl)propionic acid is replaced in theabove procedure by L-aamino a (3,4 dimethoxybenzyl)propionitrile orL-aamino on (3,4-dimethoxybenzyl)propionitrile or L-aamino a (3,4dimethoxybenzyl)propionamide, the product obtained is L a (3,4dihydroxybenzyD-uhydrazinopropionitrile or L a (3,4 dihydroxybenzyl)-u-hydrazinopropionamide.

EXAMPLE 2 To a mixture of 39.1 g. (0.1 mole) of D-a-amlHO-a-(3,4dibenzyloxybenzyl)propionic acid in 200 ml. of acetic acidcontaining 10% by weight of hydrogen bro mide is added 10.35 g. (0.15mole) of sodium nitrate in 20 ml. of water 5-10 C. The mixture isstirred for two hours at 515 C., then cautiously with stirring warmed to50 C. The mixture is filtered through sintered glass, the filtrateconcentrated in vacuo. The residue is taken up in chloroform, washedwith water, dried over magnesium sulfate and concentrated to dryness invacuo to obtain D oz bromo on (3,4-dibenzyloxybenzyl)- propionic acid.

A mixture of D a bromo a (3,4-dibenzyloxybenzyl)propionic acid (45.5 g.,0.1 mole) in diglyme (300 ml.) is hydrogenated at l atrn. of hydrogenand room temperature over 1.5 g. of platinum oxide until the uptake is 2moles of hydrogen. The mixture is concentrated to dryness in vacuo andthe residue extracted with methanol and filtered. The methanolicfiltrate is concentrated to dryness in vacuo and the residue is D abromo a (3,4- dihydroxybenzyl)propionic acid.

To a solution of 27.5 g. (0.1 mole) of D-u-brOmO-a-(3,4-dihydroxybenzyDpropionic acid in 200 ml. of methanol is added 5.0g. of 96% hydrazine. The mixture is refluxed for 2 hours. On cooling,the mixture is concentrated to dryness in vacuo, the residue taken up inchloroform- Water, the chloroform solution washed with water andsaturated salt solution and the chloroform extract dried over magnesiumsulfate. The mixture is concentrated to dryness to obtain L a(3,4-dihydroxybenzyl)-a-hydrazinopropionic acid (M.P. 208 dec.).

The starting material for this synthesis is obtained as follows: D aacetylamino a (3,4-dibenzyloxybenzyl) propionitrile (41.6 g., 0.1 mole)is added at 10 C. to a saturated solution of hydrogen chloride in water.After the mixture is allowed to stand overnight at 0 C. it isconcentrated to an oil in vacuo. Under nitr gen t e am de 5 (residue) isrefluxed with 500 ml. of 2 N hydrochloric acid for 5 hours.

The mixture is concentrated to dryness in vacuo at 50 C. taken up in 200ml. of absolute ethanol, filtered and the filtrate adjusted to pH 6.4with diethylamine. The crude product is recrystallized frommethanol-water to yield D a amino a (3,4-dibenzyloxybenzyl)propionicacid.

EXAMPLE 3 When hydrazine is replaced in the above examples byN-sodiohydrazine, the corresponding product is obtained.

When hydrazine is replaced in the above examples by N-acetylhydrazine,the product obtained is the N-acetyl derivative which may be hydrolyzedwith acid as above to obtain the corresponding product.

When potassium iodide in the above example is replaced with the silversalt of benzcnesulfonic acid, methanesulfonic acid or o-, morp-toluenesulfonic acid, the corresponding a-benzenesulfonyl,a-methylsulfonyl, thecorresponding a-benzenesulfonyl, a-methylsulfonyl,or a-(o-, mor p-tolylsulfonyl) compound is prepared. These(it-substituted compounds may then be reacted with the hydrazine asabove to obtain the corresponding product. i

What is claimed:

1. A compound of the formula:

X is chloro, brorno, or iodo;

R is hydroxy, lower alkoxy, aralkoxy selected from the group consistingof benzyloxy, diphenylmethyloxy, trityloxy, naphthylmethyloxy,o-methylbenzyloxy, 3,4- veratryloxy and 4,4,4"-trimethoxytrityloxy;

R is hydrogen or lower alkyl;

R is hydrogen or lower alkyl; and

R is carboxy.

260-465 E, 470, 471 A, 515 A, 518 R, 519, 520, 521 A, 562 H, 999

